The Udall Center for Excellence in Parkinson Disease Research at the Mayo Clinic is an integrated, multidisciplinary research program of neurologists, neuropsychologists, geneticists, neuropathologists and basic scientists in the study of the "Genetics and Molecular Biology of Parkinsonism." The Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section and longitudinal studies of Parkinson disease (PD) and dementia with Lewy bodies (DLB) for the clinical material used in the research projects, as well as strong institutional commitment to PD research. The research proposed is highly synergistic despite the wide range of expertise and scientific background of the members of the Udall team. Each member of the team brings unique knowledge and skill sets to the mission, and together we are greater than the sum of the parts. The work proposed builds upon highly successful and productive cores that have been working together for over a decade. The clinical, genetic and pathologic resources are rivaled by few centers. The Mayo Udall Center is a unique complement to the Udall Center program. Success of our Udall Center has been based upon building successful collaborations and generous sharing of resources and data. This proposal has the overarching goal to better understand Lewy-related PD, which is the most common form of PD. Lewy bodies are also the hallmark of DLB and PD with dementia (PDD). How PDD and DLB relate to each other is unknown, but this non-motor complication of PD is of increasing interest to the Parkinson community. Strengths of our Udall Center are the large collection of multi-incident PD families, a proven track record of success in discovery of PD genes and a large collection of PD, PDD and DLB brains in a well annotated brain bank. The research proposal has three projects and five cores: Project 1. "Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD," (PL: Matthew J. Farrer, PhD);Project 2. "Identification of candidate therapeutics for a-synuclein aggregation and cytotoxicity," (PL: Shu-Hui C. Yen, PhD);Project 3. "Molecular pathology of Lewy-related cognitive dysfunction," (PL: Dennis W. Dickson, MD);Core A. Administrative (CL: Dennis W. Dickson, MD);Core B. Clinical (CL: Zbigniew K. Wszolek, MD);Core C. Genetic (CL: Matthew J. Farrer PhD);Core D. Neuropathology (CL: Dennis W. Dickson MD) and Core E. Education and Outreach (CL: Ryan J. Uitti, MD). PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is one of the leading causes of neurologic disability. Understanding its cause through genetic studies will lead to animal and cell culture models to develop treatments for PD. With advances in therapies for motor abnormalities in PD, there is increasing interest in understanding non-motor features of PD, including dementia, which is a focus of research. PROJECT 1 Principal Investigator: Matthew J. Farrer, Ph.D. Title: Identification of genetic risk factors that predict disease onset, susceptibility and progression of PD Description (provided by applicant): Work from our past Udall Center application (2004-2009) provides compelling genetic, genomic and biochemical evidence that over-expression of wild-type a-synuclein is a major risk factor for Lewy body disease. Past genetic discovery has immediately improved diagnoses for rare families, and has lead to industry-sponsored translational programs in RNA interference targeting the a-synuclein gene. However, our (PD, PDD, DLB and MSA), and the role of a-synuclein is in its infancy. Project 1 has four aims to addr s these issues: Aim 1 Exonic sequencing of multi-incident family with clinical parkinsonism and autopsy confirmed Lewy body disease. As our preliminary data illustrates, the methods used provide a rapid and cost effective way to identify novel gene mutation(s) in disease. Aim 2 is for comprehensive SNCA genomic capture and re-sequencing of asynucleinopathies, to enable comparative genetic association studies of clinical and pathologic phenotypes across a range of Lewy body disorders. We need to identify the precise variants that influence disease risk, and their molecular mechanism. Work in Aim 3, using a subset of the best characterized samples, will provide complementary data from whole genome transcriptome analysis in a-synucleinopathies. Lastiy, Aim 4 will characterize the role of endogenous miRNA in the regulation of a-synuclein expression. The project could not be accomplished outside of a Center;it rests heavily on resources and expertise offered by Cores B, C and D, and will reciprocally inform research in Projects 2 &3. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases. We aim to provide a mechanistic understanding of the pathogenesis of Lewy body disorders through gene discovery, and for a-synuclein and its homologues, exploiting advances in next-generation sequencing methods. Public Health Relevance: Novel Parkinson disease (PD) genes identified by this Project in families with PD will provide a window into the cause of PD. Since a-synuclein is the major protein abnormality in PD, a comprehensive study of variability in the gene for a-synuclein will lead to new future therapies for PD.